It is an object of the invention to provide the novel steroids of formula I and their non-toxic, pharmaceutically acceptable acid addition salts and a novel process and novel intermediates for their preparation.
It is another object of the invention to provide novel compositions and a method for controlling fertility in male warm-blooded animals.
These and other objects and advantages of the invention will become obvious from the following detailed description.
The novel 20-substituted steroids of the invention are selected from the group consisting of a compound of the formula 
wherein R1 and R2 are individually selected from the group consisting of alkyl of 1 to 12 carbon atoms and aralkyl of 7 to 15 carbon atoms or taken together form a saturated heterocycle of 5 to 6 ring members optionally having a second ring heteroatom selected from the group consisting of sulfur, oxygen and nitrogen. R3 is an xcex1-alkyl of 1 to 8 carbon atoms, n is an integer from 2 to 15, R4 is alkyl of 1 to 12 carbon atoms, R5 is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms and acyl of an organic carboxylic acid of up to 12 carbon atoms and the wavy lines indicate that the 17- and 20-asymmetrical centers are independent of the absolute R and S configurations and their non-toxic, pharmaceutically acceptable acid addition salts.
Examples of R1, R2, R4 and R5 as alkyl of 1 to 12 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl-butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl-pentyl, 3-ethyl-pentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl and n-decyl, preferably methyl, ethyl or isopropyl. When R1 and R2 is aralkyl of 7 to 15 carbon atoms, it is preferably benzyl or phenethyl.
Examples of R1 and R2 forming with the nitrogen to which they are linked a saturated heterocycle with 5 or 6 ring members optionally containing another hetero ring atom chosen from oxygen, nitrogen and sulfur are piperidino, morpholino, thiomorpholino, piperazino and pyrrolidino.
Examples of R3 as alkyl of 1 to 8 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl-phenyl, 2,3-dimethyl-butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl-pentyl and 3-ethylpentyl, preferably methyl.
Examples of acyl of an organic carboxylic acid of up to 12 carbon atoms are acetyl, propionyl, butyryl, benzoyl, valeryl, hexanoyl, acryloyl and crotonoyl as well as formyl.
Examples of acids for the formation of non-toxic, pharmaceutically acid addition salts are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkane sulfonic acids such as methane or ethane sulfonic acid, arylsulfonic acids such as benzene or p-toluene sulfonic acid and arylcarboxylic acids. The addition salts of hydrochloric acid are preferred.
Among the preferred compounds are those of formula I wherein n is 2 and those of the formula 
wherein R1 and R2 are defined above and their non-toxic, pharmaceutically acceptable acid addition salts.
Specific preferred compounds of formula I are (20R) (8xcex1,9xcex2,13xcex1,14xcex2,17xcex1) 20-[((dimethylamino)-ethyl)-amino]-19-nor-xcex941,3,5(10)-pregnatrien-3-ol, (20S)(8xcex1,9xcex2,13xcex1,14xcex2,17xcex1) 20-[((dimethylamino)-ethyl)-amino]-19-nor-xcex941,3,5(10)-pregnatrien-3-ol, (20R)(8xcex1,9xcex2,13xcex1,14xcex2,17xcex2) 20-[((dimethylamino)-ethyl)-amino]-19-nor-xcex941,3,5(10)-pregnatrien-3-ol, (20S) (8xcex1,9xcex2,13xcex1,14xcex2,17xcex2) 20-[((dimethylamino)-ethyl)-amino]-19-nor-xcex941,3,5(10)-pregnatrien-3-ol, as well as their acid addition salts. Most preferred is (20S) (8xcex1,9xcex2,13xcex1,14xcex2,17xcex1) 20-[((dimethylamino)-ethyl)-amino]-19-nor-xcex941,3,5(10)-pregnatrien-3-ol and its acid addition salts.
The novel process of the invention for the preparation of the compounds of formula I comprises subjecting a compound of the formula 
wherein R3 is defined as above to an acylation agent or alkylation agent to obtain a compound of the formula 
wherein R3 is defined as above and Rxe2x80x25 is alkyl of 1 to 12 carbon atoms or acyl of an organic carboxylic acid of up to 12 carbon atoms, reacting a compound of formula II or IIA with a cyanidation agent to form a compound of the formula 
in which R3 and R5 have the same meanings as above and in which the wavy line indicates that the product is presented in the form of pure stereoisomers (17xcex1-OH, 17xcex2-CN) or (17xcex1-CN, 17xcex2-OH) or in the form of a mixture thereof, subjecting the latter to a dehydration reaction to obtain a compound of the formula 
in which R3 and R5 have the above meanings, reducing the 16-17 double bond to obtain a compound of the formula 
wherein the wavy line indicates that the xe2x80x94CN is in position 17xcex1 or 17xcex2, or in the form of a 17xcex1 and 17xcex2 mixture, and R3 and R5 have the above meanings, reacting the latter with an organometal reagent of R4 as defined above, then to the action of an acid hydrolysis agent to obtain a compound of the formula 
wherein R3, R4 and R5 have the above meanings and in which the wavy line indicates that the xe2x80x94COR4 is in position 17xcex1 or 17xcex2, or in the form of a 17xcex1 and 17xcex2 mixture, reacting the latter with a hydroxyl-amine salt to obtain a compound of the formula 
wherein R3, R4 and R5 have the above meanings and in which the wavy line indicates that xe2x80x94C(R4)xe2x95x90Nxe2x80x94OH is in 17xcex1 or 17xcex2 position or in the form of a 17xcex1 and 17xcex2 mixture, and the oxime is in the syn or anti position, or in the form of a syn and anti mixture, reducing the oxime to obtain a compound of the formula 
wherein the wavy line indicates that xe2x80x94NH2 is in 20R or 20S position or in the form of a 20R and 20S mixture, and R3, R4 and R5 have the above meanings, reacting the latter with an acyl halide of the formula
Xxe2x80x94COxe2x80x94(CH2)nxe2x80x2xe2x80x94NR1R2
wherein X is halogen, R1 and R2 are as defined above, nxe2x80x2 is equal to nxe2x88x921, n being defined as above, then, optionally to a selective hydrolysis in the 3-position of the diacylated compound formed to obtain a compound of the formula 
wherein the wavy lines, R1, R2, R3, R4, R5 and nxe2x80x2 have the above meanings, reducing the keto group of the said amide, and optionally to one or more of the following reactions in any order:
acylation in position 3,
alkylation in position 3,
saponification of acyloxy in position 3,
separation of the different stereoisomers,
salification with an organic or mineral acid to obtain the compound of formula I.
The acylation agent is preferably a carboxylic acid derivative, for example acid chloride or an anhydride in the presence of a base such as pyridine. The optional alkylation is carried out by the usual methods with an alkylation agent such as preferably an alkyl halide like alkyl iodide or alkyl sulfate.
The cyanidation agent is preferably sodium or potassium cyanide and the cyanidation reaction is preferably carried out in a lower alcohol such as methanol in the presence of acetic acid. The dehydration reaction can be carried out using a dehydration agent such as phosphorus oxychloride in pyridine.
The reduction of the 16-17 double bond can be carried out either by catalytic hydrogenation with the hydrogenation agent being hydrogen in the presence of catalysts such as palladium on charcoal, or a rhodium reagent such as Wilkinson reagent, or by the action of sodium borohydride in ethanol, or by the action of magnesium in methanol. This reduction is either stereospecific and allows the CH-substituent to be obtained in position 17xcex1 or in position 17xcex2, or it is non-stereospecific in which a mixture of stereoisomers (17xcex1+17xcex2) is obtained which is optionally separated by standard methods such as crystallization or chromatography.
The organometal reagents which are derivatives of R4 are standard reagents such as an organolithium compound (R4xe2x80x94Li), an organomagnesium compound (R4xe2x80x94Mgxe2x80x94X) with X being halogen chosen from Cl, Br and I, preferably Br.
The acid hydrolysis reaction which follows the reaction with the organometal allows the intermediate imine formed to be hydrolyzed which hydrolysis is carried out under standard conditions for imine hydrolysis in an acid medium such as hydrochloric acid, oxalic acid or acetic acid.
Formation of the oxime of formula VII is preferably carried out by the action of hydroxylamine hydrochloride in the presence of a base such as pyridine, sodium hydroxide or sodium carbonate.
The reduction of the product of formula VII can be carried out by different methods such as catalytic hydrogenation with, as hydrogenation reagent, hydrogen in the presence of catalysts such as palladium on charcoal or platinum dioxide, by the action of zinc in an acetic medium, by sodium in an alcohol such as ethanol or n-propanol, or also by the addition of diborane in diglyme. This reduction is either stereospecific and allows the product in position 20R or in position 20S to be obtained, or it is non-stereospecific wherein a mixture of 20R+20S stereoisomers is obtained which is optionally separated by standard methods such as crystallization or chromatography.
The condensation of the compound of formula Xxe2x80x94COxe2x80x94(CH2)nxe2x80x2xe2x80x94NR1R2 in which X is halogen chosen from Cl, Br and I and nxe2x80x2, R1 and R2 are as described previously with the compound of formula VIII is carried out in a basic medium, preferably in an aprotic dipolar solvent such as dimethylformamide (DMF). The reaction is preferably carried out in a triethylamine/dimethylformamide (TEA/DMF) medium.
The selective hydrolysis of the O-acyl compound which is optionally formed intermediately is carried out under the usual conditions using an agent which can be an alkaline base such as sodium hydroxide or potassium hydroxide in a lower alcohol such as methanol or ethanol.
The reduction of the keto group of the amide of formula IX is carried out for example by means of a metal hydride such as lithium aluminum hydride. (AlLiH4) in an aprotic polar solvent such as tetrahydrofuran (THF) or ether or by means of alkali metal borohydrides such as sodium borohydride (NaBH4) in the presence of acids such as acetic acid.
If desired and if necessary, the acylation or alkylation reactions of the 3 xe2x80x94OH group are carried out by the methods as described previously. The optional saponification reaction is preferably carried out in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, potassium terbutylate or lithium acetylide in ethylene amine. The saponification reaction takes place preferably in a lower alcohol such as methanol or ethanol.
The optional separation of the different stereoisomers is carried out by standard methods of crystallization or chromatography. The salification with an acid is carried out under the usual conditions preferably with hydrochloric acid for example in an ethereal solution.
During the action of a cyanidation agent leading to the product of formula III, with an organometal reagent leading to the product of formula VI or of the hydroxylamine salt leading to the product of formula VII, a product of formulae III, VI or VII can be obtained in which the acyloxy group is hydrolyzed.
The invention extends to a process as defined previously in which the product of formulae III, VI or VII in which the acyloxy group has been hydrolyzed, is optionally reacylated.
The products of formulae V, VI, VII, VIII and IX are optionally obtained in the form of a mixture of stereoisomers which can optionally be subjected to operations which separate these stereoisomers. The invention extends to a process as defined previously in which the different stereosisomers obtained during preparation processes of the products of formulae V, VI, VII, VIII and IX are optionally separated.
The compositions of the invention for controlling fertility in male warm-blooded animals are comprised of an amount of a compound of formula and its non-toxic, pharmaceutically acceptable acid addition salts sufficient to control fertility and an inert pharmaceutical carrier. The compositions may be in the form of tablets, dragees, capsules, granules, suppositories, gels, creams, implants, microspheres, patches and injectable solutions or suspensions or pessaries and particularly vaginal pessaries.
Examples of suitable inert pharmaceutical carriers are talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and preservatives.
The compositions of the invention have 1) a strong affinity for the Sigma receptors (see the pharmacological tests) or 2) an activity vis-à-vis the influx of the calcium into the spermatozoid. The results of tests show that among the products which fix to the Sigma receptors, certain act by stimulating the influx of calcium into the spermatozoid and others by inhibiting the influx of calcium stimulated or not by progesterone, a molecule described as binding to the Sigma receptor.
The products of formula I having an agonist activity stimulate the influx of calcium into the spermatozoid. The corresponding compositions of the invention can be used in the treatment of certain forms of sterility characterized by an insufficient fertilizing power of the spermatozoids.
The products of formula I having an antagonist activity inhibit the influx of calcium into the spermatozoid. The corresponding compositions of the invention are therefore of use in controlling the acrosomial reaction and consequently affect the fertilizing power of the spermatozoid. They can therefore be used, as a contraceptive and in particular as a male contraceptive.
They can also be used in the veterinary domain as a male contraceptive in domestic animals (dogs, cats . . . ) or to limit the proliferation of any pests, in particular rodents or pigeons.
The method of the invention for controlling fertility in male warm-blooded animals comprises administering to male warm-blooded animals an amount of a compound of formula I or its acid addition salts in an amount sufficient to control fertility. The compounds may be administered orally, rectally or parenterally or locally, particularly for a woman, for example by percutaneous route or by injection particularly in the veterinary field and the usual daily dose is 0.10 to 13.5 mg/kg depending on the specific compound, method of administration and the condition treated.
The compound of formula II is available by the processes described by Hutchinson et al., Tetrahedron Letters, 1985, Vol. 26(15), pp. 1819-1822 and Smith et al, J. Am. Chem. Soc., 1966, pp. 3120-3128.
The intermediates of formulae IIA, III, IV, V, VI, VII, VIII and IX are novel and a part of the invention with the exception of compounds of formula IIA in which Rxe2x80x25 is an alkyl group containing at most 12 carbon atoms.
In the following examples, there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.